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Endocrine and metabolic Musculoskeletal

Gout

Last revised in June 2023

Gout is a disorder of purine metabolism characterized by a raised uric acid level in the blood (hyperuricaemia) and the deposition of urate crystals

Gout: Summary

Gout is a type of arthritis caused by monosodium urate crystals forming inside and around joints, causing sudden flares of severe pain, heat, and swelling.
- Any joint can be affected, but it most commonly affects distal joints, including toes, knees, ankles, and finger joints.
Hyperuricaemia is the most important risk factor in the development of gout.
Other risk factors for hyperuricaemia and gout include:
- Increasing age.
- Family history of hyperuricaemia and gout.
- Genetics.
- Excess body weight or obesity.
- Male sex.
- Diet — consumption of excess alcohol, sugary drinks, meat, and seafood.
- Menopausal status in women — gout is more common in postmenopausal women.
- Some medicines (for example, diuretics, low-dose aspirin, or ciclosporin).
- Comorbidities such as chronic kidney disease (CKD), hypertension, and diabetes mellitus.
Complications include:
- Cardiovascular disease and cardiovascular mortality.
- Chronic arthritis.
- Chronic kidney disease.
- Joint damage.
- Reduced quality of life.
- Renal stones.
- Tophi.
Gout should be suspected in people presenting with any of the following:
- Rapid onset of severe pain together with redness and swelling in one or both metatarsophalangeal joints.
- Tophi.
Assessment of gout should include taking a medical history, examining the person, and measuring the serum urate level.
- A serum urate level of 360 micromol/L (6 mg/dL) or more confirms the diagnosis.
Management of an acute attack of gout should include:
- Offering a nonsteroidal anti-inflammatory drug, colchicine, or a short course of oral corticosteroid.
- Giving appropriate self-care advice.
Urate-lowering therapy (ULT) using a treat-to-target strategy should be offered to people with gout who have:
- Multiple or troublesome flares.
- CKD stages 3 to 5 (glomerular filtration rate [GFR] categories G3 to G5).
- Diuretic therapy.
- Tophi.
- Chronic gouty arthritis.
The option of ULT should be discussed with all other people experiencing a first or subsequent flare.
Allopurinol or febuxostat should be offered first-line taking into account the person's preferences and comorbidities and started at a low dose.
The benefits and risks of taking medicines to prevent gout flares when starting or titrating ULT should be discussed and colchicine, NSAIDs, or corticosteroid offered if appropriate.
The serum urate level should be checked monthly until is it within the target range and annual monitoring considered thereafter.
People should be referred immediately, according to the local care pathway if septic arthritis is suspected.
Referral to a rheumatology service should be considered if:
- The diagnosis of gout is uncertain.
- The response to treatment has not been adequate or the treatment is not tolerated.
- Treatment is contraindicated.
- They have CKD stages 3b to 5 (GFR categories G3b to G5).
- They have had an organ transplant.

Have I got the right topic?

From age 16 years onwards.

This CKS topic is largely based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], the British Medical Journal (BMJ) Best Practice guide Gout [BMJ, 2021], the 2018 updated European League Against Rheumatism (EULAR) evidence-based recommendations for the diagnosis of gout [Richette, 2020], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], the British Society for Rheumatology Guideline for the Management of Gout [Hui, 2017], and the 2020 American College of Rheumatology Guideline for the management of gout [FitzGerald, 2020].

This CKS topic covers the management of asymptomatic hyperuricaemia and gouty arthritis in adults.

This CKS topic does not cover the management of other crystal-related arthropathies (e.g. pseudogout), gout in children, uric acid renal stones, urate nephropathy, or the prevention of hyperuricaemia in people who are being treated for haematological malignancies.

There are separate CKS topics on NSAIDs - prescribing issues, Osteoarthritis and Rheumatoid arthritis.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare.

How up-to-date is this topic?

Changes

June 2023 — minor update. Information on cautions when prescribing febuxostat updated in line with MHRA drug safety update to advise caution when prescribing febuxostat to people with cardiovascular disorders, particularly in those with evidence of high urate crystal and tophi burden or those initiating urate-lowering therapy.

Previous changes

June 2022 — reviewed. A literature search was conducted in June 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. There have been minor structural changes to this topic and recommendations on management of acute gout and prevention of gout have been updated in line with national guidelines.

November 2017 to February 2018 — reviewed. A literature search was conducted in October 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of the topic. The recommendations on medical management of acute gout and prevention of gout have been amended and are in line with national guidance. Minor structural changes have been made to the topic.

January 2018 — minor update. Information on screening before starting treated with allopurinol updated as per the manufacturer's Summary of Product Characteristics.

January 2017 — minor update. Information that blood creatine phosphokinase increase is a rare adverse reaction of Adenuric120 mg film-coated tablets in line with a change to the manufacturer's Summary of Product Characteristics.

December 2016 — minor update. Information that colchicine is contraindicated in people taking ritonavir has been added to this topic, in line with a change to the manufacturer's Summary of Product Characteristics.

July 2016 — minor update. The recommended maximum alcohol intake has been updated in line with the Alcohol Guidelines Review published by the Department of Health (2016).

April 2015 — minor update. A link to the CKS topic Analgesia - mild-to-moderate pain has been inserted.

February 2015 — minor update. Probenecid has been discontinued. References to probenecid have been removed from the topic.

February 2014 — minor update to the prescribing information section for allopurinol.

July 2013 — minor update. The text has been updated to reflect recent guidance from the MRHA regarding diclofenac.

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic.

January 2013 — minor update. Black triangle status removed from febuxostat, and advice from the Medicines and Healthcare products Regulatory Agency regarding hypersensitivity reactions of febuxostat has been inserted.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic.

August 2012 — reviewed. A literature search was conducted in August 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made.

March 2012 — minor update. Updated to include the recommendation from the House of Commons Science and Technology Committee that people should have at least two alcohol-free days per week.

September 2011 — minor update. Update of febuxostat to include post marketing reports of skin rashes and hypersensitivity reactions highlighted in the updated Summary of Product Characteristics.

May 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic.

October 2010 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

July 2010 — updated to include the option of using febuxostat for the management of chronic gout for people who are intolerant of allopurinol, or for whom allopurinol is contraindicated. This is in line with National Institute for Health and Clinical Excellence technology appraisal guidance Febuxostat for the management of hyperuricaemia in people with gout. In addition, in people at risk of cardiovascular adverse events, ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line NSAIDs.

December 2009 — minor update. Triamcinolone acetonide (Kenalog^®) pre-filled syringes have been discontinued. Prescription replaced with triamcinolone acetonide 40 mg/1 mL vials.

July to November 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence. The recommendations have been revised to be in-line with the British Society for Rheumatology and the British Health Professionals guidelines for the management of gout published in 2007. The dose and duration of recommended drug treatments have been updated to be in-line with current practice, in particular, for oral prednisolone.

November 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has recently reminded prescribers that colchicine has a narrow therapeutic window and is extremely toxic in overdose

June 2009 — minor update. The intra-articular corticosteroid prescriptions have been updated.

February 2009 — minor typographical correction.

July 2005 — update to text discussing nonsteroidal anti-inflammatory drugs (NSAIDs) in the Prescribing information section.

April 2005 — reviewed.

April 2002 — reviewed.

April 1999 — written. Validated in July 1999 and issued in August 1999.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 June 2022.

HTAs (Health Technology Assessments)

No new technology appraisals published since 1 June 2022.

Economic appraisals

No new economic appraisals relevant to England since 1 June 2022.

Systematic reviews and meta-analyses

Banerjee, M., Pal, R., Maisnam, I., et al. (2023) Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: A meta-analysis and meta-regression of randomized controlled trials. Diabetes, Obesity and Metabolism. https://dom-pubs.pericles-prod.literatumonline.com/ [Abstract]

Primary evidence

McCormick, N., Yokose, C., Wei, J., et al. (2023) Comparative Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for Recurrent Gout Flares and Gout-Primary Emergency Department Visits and Hospitalizations. Annals of Internal Medicine. [Abstract]

New policies

No new national policies or guidelines since 1 June 2022.

New safety alerts

No new safety alerts since 1 June 2022.

Changes in product availability

No changes in product availability since 1 June 2022.

Goals and outcome measures

Goals

To support primary healthcare professionals to:

Make a diagnosis of gout.
Enable the person to understand the nature of gout, and the risks and benefits of the various drug and dietary treatment options.
Relieve the pain and inflammation of an acute attack of gout promptly.
Reduce the risk of recurrent attacks of gout — if not outweighed by the risks of treatment.
Minimize the risks of developing complications of gout, such as joint damage, renal stones, and urate nephropathy.

Outcome measures

No audit criteria were found during the review of this topic.

Audit criteria

No audit criteria were found during the review of this topic.

QOF indicators

No QOF indicators were found during the review of this topic.

QIPP - Options for local implementation

No QIPP indicators were found during the review of this topic.

NICE quality standards

No NICE quality standards were found during the review of this topic.

Background information

What is it?

Gout is a type of arthritis caused by monosodium urate crystals forming inside and around joints, causing sudden flares of severe pain, heat, and swelling.
Any joint can be affected, but it most commonly affects the distal joints, such as toes, knees, ankles, and finger joints.
There are four clinical phases of gout:
- Asymptomatic hyperuricaemia — the risk of developing gout increases with the degree of hyperuricemia.
- Acute gout — in almost all initial episodes a single peripheral joint is affected, most commonly the metatarsophalangeal joint.
- Intercritical gout — after resolution of the first attack the second attack may occur within one year and chronic symptoms develop within 10 years.
- Chronic tophaceous gout — large crystal deposits (tophi) produce irregular firm nodules and chronic joint damage.
Gout may present without hyperuricaemia, and hyperuricaemia may occur without gout.

[Roddy, 2020; NICE, 2022]

What are the causes and risk factors for gout?

Urate is a metabolite of purines and is the ionised form of uric acid at physiological pH.
- 70% of urate is excreted by the kidneys and 30% by the gastrointestinal tract.
Hyperuricaemia (a high urate level) is the most important risk factor for developing gout. The level of urate directly correlates with risk of disease (see Table 1). However, gout can occur in people with normal plasma urate levels and around 95% of people with hyperuricaemia never develop gout.
- Hyperuricaemia is usually due to impaired renal excretion of urate. About 90% of people with hyperuricaemia are under-excretors of urate, about 10% are over-producers of urate, and some people are both under-excretors and over-producers of urate.
Risk factors for hyperuricaemia and gout include:
- Comorbidities such as chronic kidney disease (CKD), hypertension, diabetes mellitus, hyperlipidaemia, osteoarthritis, lymphoproliferative/myeloproliferative disorders, and severe exfoliative psoriasis.
- Diet — consumption of excess alcohol, sugary drinks, meat, and seafood.
- Excess body weight or obesity.
- Family history of hyperuricaemia and gout.
- Genetics — for example, glycogen storage diseases and Lesch-Nyhan syndrome, which are associated with urate overproduction, hyperuricaemia and accelerated purine synthesis.
- Male sex.
- Menopausal status in women — gout is more common in postmenopausal women.
- Older age.
- Some medicines (for example, diuretics, low-dose aspirin, ciclosporin).

Table 1. Annual incidence of gout categorized by plasma urate level.

Plasma urate level (micromol/L)	Annual incidence
420–470	0.4%
480–530	0.8%
540–590	4.3%
> 590	7%
Note: plasma urate level is interchangeable with serum uric acid level (SUA).
Data from: [Campion et al, 1987]

[Singh et al, 2011; Roddy, 2013; Hui, 2017; Richette, 2020; BMJ, 2021; NICE, 2022]

How common is it?

Gout is the most common inflammatory arthritis and is increasing in prevalence worldwide [Richette, 2020; Safiri, 2020].
It is more common in men aged over 30 years and postmenopausal women [NICE, 2022].
Prevalence increases with age, plateauing at around 80 years of age. Gout is rare in people younger than 20 years of age [Kuo, 2015; BMJ, 2021; NICE, 2022].
A study of UK general practice in 2012 found that [Kuo, 2015]:
- The prevalence of gout was 2.49% (increased from around 1.4% in 1999).
- The incidence of gout was 1.77 per 1000 person-years.
- The overall ratio of men to women was 4.3:1.
Gout prevalence varies in different populations and is reported at a higher prevalence in Oceania, North America and among indigenous populations such as Maori, Aboriginals and Inuit [Wijnands, 2015].
- It is thought that the higher prevalence reported in North America may be attributed to higher rates in ethnic groups such as African Americans and Filipinos due to both increasing rates of hypertension and adoption of Western diet in these populations [Wijnands, 2015].

What are the complications?

Complications of gout include:
- Chronic arthritis — left untreated, about 2% of people with gout develop severe debilitating arthritis (around 20 years after the first attack) [BMJ, 2021].
- Joint damage.
- Reduced health-related quality of life — poorly controlled gout leads to absences from work, healthcare use, and reduced social participation.
- Renal stones — these are found in around 14% of people with gout [Roughley, 2015].
- Tophi — these occur in approximately 50% of people with untreated gout after 10 years. This increases to 72% after 20 years [BMJ, 2021].
  - Tophi may create problems with activities of daily living, become inflamed, exude tophaceous material, or develop secondary infection, and adversely impact on quality of life [Dalbeth, 2016].
Hyperuricaemia is associated with an increased risk of:
- Cardiovascular disease and cardiovascular mortality.
  - A systematic review and meta-analysis of 26 studies and almost 1 million people with gout found that the prevalence of myocardial infarction was 2.8%, heart failure was 8.7%, venous thromboembolism was 2.1%, cerebrovascular accident was 4.3% and hypertension was 63.9% [Cox, 2021].
- Chronic kidney disease (CKD) — almost 25% of people with gout have CKD stages 3 to 5 (glomerular filtration rate [GFR] categories G3 to G5) [NICE, 2022].

[Dalbeth, 2016; Hui, 2017; BMJ, 2021; NICE, 2022]

What is the prognosis?

Acute attacks are self-limiting and left untreated usually resolve spontaneously over 5-15 days, often with pruritus and desquamation of overlying skin.
In people not taking urate-lowering therapies (ULT), the risk of recurrence is 62% in the first year, 78% in the second year, and 84% in the third year after the first attack.
- Recurrent acute episodes and the development of chronic gout lead to progressive joint damage, chronic pain, and disability.
Appropriate treatment can suppress gout attacks and their recurrence, and prevent long-term consequences of the disease.

[Roddy, 2020; BMJ, 2021]

Diagnosis of gout

When should I suspect a person has gout?

Suspect gout in people presenting with any of the following:
- Rapid onset (often overnight) of severe pain together with redness and swelling in one or both metatarsophalangeal (MTP) joints.
- Tophi — these are hard cutaneous nodules of sodium urate crystals which can appear on the extensor surfaces of affected joints, Achilles tendons, dorsal aspect of hands and feet and in the helix of the ears. They suggest longstanding, untreated gout.
Consider gout in people presenting with rapid onset (often overnight) of severe pain, redness or swelling in joints other than the first MTP joints (for example midfoot, ankle, knee, hand, wrist or elbow).
Consider chronic gouty arthritis in people presenting with chronic inflammatory joint pain.

Basis for recommendation

How should I assess a person with suspected gout?

Take a detailed medical history, and ask about:
- Current symptoms:
  - Joints affected — gout typically affects the first metatarsophalangeal joint (big toe). This is the site of the first attack in 50% of people and over 70% of people at some point. It is also common in the midfoot, ankle, knee, fingers, wrist and elbow joints although any joint can be affected. Gout is usually monoarticular but can be oligoarticular or rarely polyarticular.
  - Symptom severity and speed of onset — rapid onset of severe pain with associated swelling, redness, warmth and tenderness usually reaches maximum intensity within 24 hours.
  - The frequency and duration of attacks.
- Previous attacks, and any previous drug interventions.
  - A history of previous self-limiting (7-14 days) attacks supports the diagnosis.
- Dietary habits.
- Their ability to mobilize and any impact on work and functioning.
- Family history of gout, hyperuricaemia, nephrolithiasis or renal disease.
- Comorbidities and risk factors.
Examine the person and look for:
- Warm, red and swollen joints — examine all joints as any joint can be affected.
  - Lower limb joints are affected more frequently than upper limb joints.
- Tophi (firm, white nodules under translucent skin).
  - Tophi usually occur over extensor joint aspects such as the elbow or knee, or Achilles tendon. They can occur in other areas such as the helix of the ears or dorsum of hands or feet.
  - They are usually pain-free but can become inflamed, infected or ulcerated, or discharge white material.
  - Tophi occur in about 50% of people after 10 years and around 72% of people after 20 years, although in atypical cases, tophaceous disease can be the initial presentation without any flares.
- Tenderness and limited range of movement.
Assess the possibility of septic arthritis, calcium pyrophosphate crystal deposition and inflammatory arthritis.
- If septic arthritis is suspected, refer immediately according to the local care pathway.
Measure the serum urate level.

What are the American College of Rheumatology criteria for diagnosing gout?

According to the American College of Rheumatology (ACR) criteria, a diagnosis of gout is confirmed if [BMJ, 2021]:
- Monosodium urate crystals are identified in joint fluid, or
- Monosodium urate crystals are identified from tophus, or
- Six or more of the following apply:
  - More than one attack of acute arthritis.
  - Maximum inflammation developed within 1 day.
  - Monoarthritis attack, redness observed over joints.
  - First metatarsophalangeal joint painful or swollen.
  - Unilateral first metatarsophalangeal joint attack.
  - Unilateral tarsal joint attack.
  - Tophus (confirmed or suspected).
  - Hyperuricaemia.
  - Asymmetrical swelling within a joint on X-ray film.
  - Subcortical cyst without erosions on X-ray film.
  - Joint culture negative for organism during attack.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], the British Medical Journal (BMJ) Best Practice guide Gout [BMJ, 2021], the 2018 updated European League Against Rheumatism (EULAR) evidence-based recommendations for the diagnosis of gout [Richette, 2020], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], the British Society for Rheumatology Guideline for the management of gout [Hui, 2017], expert opinion in a chapter on Crystal-related arthropathies in a medical textbook [Roddy, 2020] and narrative reviews Gout [Roddy, 2013], Gout [Dalbeth, 2016], and Gout [Nuki, 2006], and what CKS considers good medical practice.

What investigations should I consider?

Measure the serum urate level in people with suspected gout.
- A serum urate level of 360 micromol/L (6 mg/dL) or more confirms the diagnosis.
  - Note: the diagnosis of gout should not be made on the presence of hyperuricaemia alone.
- If the serum urate level is below 360 micromol/L but gout is strongly suspected, repeat the serum urate level measurement in 2-4 weeks after the flare has settled.
If the diagnosis remains uncertain or unconfirmed, arrange investigations in secondary care:
- Joint aspiration and microscopy of synovial fluid.
- If joint aspiration cannot be carried out or the diagnosis remains uncertain, imaging of the affected joint with X-ray, ultrasound, or dual-energy CT may be necessary.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], and the 2018 updated European League Against Rheumatism (EULAR) evidence-based recommendations for the diagnosis of gout [Richette, 2020].

Serum urate level

Most people with gout have hyperuricaemia (serum urate level of 360 micromol/L [6 mg/dL] or more) but many people with hyperuricaemia do not have gout. If the serum urate level is below 360 micromol/L but gout is strongly suspected, an additional serum urate level measurement should be done 2 to 4 weeks after the acute flare has settled. This is because serum urate levels can be lower when a person is experiencing a gout flare [NICE, 2022].

Joint aspiration

NICE advises that joint aspiration is the gold standard test to diagnose gout when the diagnosis is uncertain — this is usually done in secondary care [NICE, 2022].
EULAR advises that demonstration of monosodium urate crystals in fluid or tophus aspirates is the gold standard for diagnosis of gout and recommends that in all people with suspected gout, synovial fluid or tophus aspirates should be analysed, and this should be undertaken by a clinician with the necessary expertise [Richette, 2020].
EULAR advises that for people in whom synovial fluid analysis is not possible, a clinical diagnosis of gout is supported by the following suggestive features [Richette, 2020]:
- Monoarticular involvement of a foot (especially the first MTP) or ankle joint.
- Previous similar acute arthritis episodes.
- Rapid onset of severe pain and swelling (at its worst in <24 hours).
- Erythema.
- Male gender and associated cardiovascular diseases and hyperuricaemia.

What else might it be?

Bursitis, tenosynovitis, cellulitis — for more information, see the CKS topics on Cellulitis - acute, Olecranon bursitis, and Pre-patellar bursitis.
Haemochromatosis.
Non-urate crystal-induced arthropathy, such as pseudogout.
Osteoarthritis — for more information, see the CKS topic on Osteoarthritis.
Psoriatic arthritis.
Reactive arthritis.
Rheumatoid arthritis — for more information, see the CKS topic on Rheumatoid arthritis.
Septic arthritis:
- Septic arthritis must be considered in any person who is systemically unwell (with or without a temperature) and an acutely painful, hot, swollen joint. It is important to diagnose septic arthritis promptly, as late recognition can be fatal. If suspected, refer for emergency joint aspiration and culture.
Trauma.

Basis for recommendation

This information is based on the British Medical Journal (BMJ) Best Practice guide Gout [BMJ, 2021], and expert opinion in a chapter on Crystal-related arthropathies in a medical textbook [Roddy, 2020], and narrative reviews Gout [Roddy, 2013], and Gout [Nuki, 2006].

Management

Scenario: Acute gout

From age 16 years onwards.

How should I manage a person with acute gout?

Acute episodes should be treated as soon as possible.
Offer one of the following first-line, taking into account the person's preferences, comorbidities and concurrent medication:
- A nonsteroidal anti-inflammatory drug (NSAID) at the maximum dose (for example, naproxen).
  - Continue the treatment until 1-2 days after the attack has resolved.
  - Consider the need to prescribe a proton pump inhibitor (PPI) for gastric protection. For more information, see the CKS topic on NSAIDs - prescribing issues.
  - Note: aspirin is not indicated for gout.
- Colchicine.
- A short course of oral corticosteroid — for example prednisolone 30-35 mg once a day for 3-5 days.
  - Note: this is an off-label use of oral corticosteroids.
Consider an intra-articular or intramuscular corticosteroid injection if NSAIDs and colchicine are not tolerated or are ineffective.
- Note: this is an off-label use of corticosteroid injection.
Advise people with gout that ice packs can also be applied to the affected joint to help alleviate pain.
Consider combining treatments if the response to monotherapy is inadequate.
Consider paracetamol as an adjunct for pain relief. For more information, see the CKS topic analgesia - mild-to-moderate pain.
Do not offer an interleukin-1 (IL-1) inhibitor to treat a gout flare unless NSAIDs, colchicine and corticosteroids are contraindicated, not tolerated or ineffective. Refer the person to a rheumatology service before prescribing an IL-1 inhibitor.
Provide tailored information to people with gout and their family members or carers (as appropriate). Explain:
- The signs and symptoms of gout.
- The causes.
- That the disease will progress without treatment as high levels of urate in the blood will lead to formation of new urate crystals.
- Any risk factors they have for gout, including genetics, excess body weight or obesity, medicines they are taking, and comorbidities such as chronic kidney disease or hypertension.
- How to manage gout flares and the treatment options available.
- That gout is a lifelong condition that will benefit from long-term urate-lowering therapy (ULT) to eliminate urate crystals and prevent flares, shrink tophi and prevent long-term joint damage.
- Where to find other sources of information and support such as local support groups, online forums and national charities.
Advise the person to:
- Rest and elevate the limb.
- Keep the joint exposed and in a cool environment.
- Consider the use of an ice pack or bed-cage.
- Return if symptoms get worse, or if there is no improvement after 1-2 days.
- Continue treatment with urate-lowering drugs (allopurinol or febuxostat) if they are already taking these.
Offer lifestyle advice.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], the British Medical Journal (BMJ) Best Practice guide Gout [BMJ, 2021], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], the British Society for Rheumatology Guideline for the management of gout [Hui, 2017], the 2020 American College of Rheumatology Guideline for the management of gout [FitzGerald, 2020], expert opinion in a narrative review Diagnosis, treatment, and prevention of gout [Hainer, 2014], the British National Formulary [BNF, 2022], and what CKS considers good medical practice.

Managing flares

Evidence shows that there is no difference between NSAIDs, colchicine or corticosteroids for most outcomes in people with gout including pain and joint tenderness and swelling. NICE does not recommend a specific NSAID, or indicate what dose should be prescribed, but advises that the choice of treatment for gout flares should take into account the person's comorbidities, co-prescriptions and preferences [NICE, 2022].
The recommendation to use a maximum dose of NSAID is based on the BSR guideline which recommends that where there is no contraindication to do so, a high dose of NSAID should be prescribed because of the severity of the pain and inflammation [Hui, 2017], and expert opinion in a medical textbook which recommends that NSAIDs should be given at the full dose [Roddy, 2020].
The recommendation to continue treatment with NSAIDs for 1-2 days after relief of symptoms is based on expert opinion in a narrative review [Hainer, 2014].
The recommendation to consider combining treatments is based on the BSR guideline which advises that if the response to monotherapy is insufficient combinations of treatment can be used [Hui, 2017], and expert opinion in a narrative review [Dalbeth, 2016].
The recommendation to consider paracetamol as an adjunct analgesic is based on expert opinion in a multinational guideline [Sivera, 2014].

Oral corticosteroid dose

The recommendation to use a dose of corticosteroid equivalent to 30-35 mg prednisolone once a day for 3-5 days is based on the EULAR guideline [Richette, 2017].

What follow up is recommended after an acute attack of gout?

Consider arranging a follow-up appointment 4-6 weeks after a gout flare has settled to:
- Measure the serum urate level.
- Provide tailored information to people with gout and their family members or carers (as appropriate). Explain:
  - The signs and symptoms of gout.
  - The causes.
  - That the disease will progress without treatment as high levels of urate in the blood will lead to the formation of new urate crystals.
  - Any risk factors they have for gout, including genetics, excess body weight or obesity, medicines they are taking, and comorbidities such as chronic kidney disease (CKD) or hypertension.
  - How to manage gout flares and the treatment options available.
  - That gout is a lifelong condition that will benefit from long-term urate-lowering therapy (ULT) to eliminate urate crystals and prevent flares, shrink tophi and prevent long-term joint damage.
  - Where to find other sources of information and support such as local support groups, online forums and national charities.
- Assess lifestyle and comorbidities (including cardiovascular risk factors and CKD).
  - Offer testing for CKD using eGFRcreatinine and albumin:creatinine ratio (ACR).
  - Provide ongoing lifestyle advice. For more information, see the CKS topic on CVD risk assessment and management.
- Review medications and discuss the risks and benefits of long-term urate lowering therapy (ULT).
  - In a person with hypertension taking a diuretic, consider changing to an alternative antihypertensive, provided that blood pressure is controlled. For more information, see the CKS topic on Hypertension.
  - In a person with heart failure, continue diuretics during an acute attack. If using a nonsteroidal anti-inflammatory drug (NSAID) for pain relief, monitor renal function closely. For more information, see the CKS topic on Heart failure - chronic.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guidelines Gout: diagnosis and management [NICE, 2022], and Chronic kidney disease: assessment and management [NICE, 2021], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], and the British Society for Rheumatology Guideline for the Management of Gout [Hui, 2017].

Screening for comorbidities

NICE recommends that as part of follow-up lifestyle and comorbidities (including cardiovascular risk factors and CKD) should be assessed [NICE, 2022].
EULAR advises that all people with gout should be screened for associated comorbidities and cardiovascular risk factors which should be addressed as an integral part of the management of gout. Hyperuricaemia and gout are independent risk factors for coronary heart disease, heart failure, stroke, peripheral arterial disease and diabetes mellitus, and for death due to cardiovascular causes. EULAR also recommends that the estimated glomerular filtration rate (eGFR) should be calculated at the time of diagnosis for CKD classification and monitored regularly in parallel with the serum urate measurement — the EULAR taskforce agreed that identifying CKD in people with gout was of major importance because of the therapeutic implications [Richette, 2017].
BSR also recommends that people with gout should be screened for cardiovascular risk factors and comorbid conditions, such as cigarette smoking, hypertension, diabetes mellitus, dyslipidaemia, obesity and renal disease and that these should be reviewed at least annually and managed appropriately [Hui, 2017].

When should I refer?

Refer the person immediately, according to the local care pathway if septic arthritis is suspected.
Refer to a specialist or seek specialist advice when:
- There is a suspicion of an underlying systemic illness (for example rheumatoid arthritis or connective tissue disorder), or gout occurs during pregnancy or in a young person (under 30 years of age).
- An intra-articular steroid injection is indicated but the facilities or expertise are not available in primary care.
- Complications are present.
- The person is at risk of adverse effects of drug treatment.
Consider referring a person with gout to a rheumatology service if:
- The diagnosis of gout is uncertain.
- The response to treatment has not been adequate or the treatment is not tolerated.
- Treatment is contraindicated.
- They have chronic kidney disease (CKD) stages 3b to 5 (GFR categories G3b to G5).
- They have had an organ transplant.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], and what CKS considers good medical practice.

Scenario: Preventing gout

From age 16 years onwards.

What drug treatment is recommended to prevent recurrent attacks of gout?

Offer urate-lowering therapy (ULT) using a treat-to-target strategy to people with gout who have:
- Multiple or troublesome flares.
- Chronic kidney disease (CKD) stages 3 to 5 (glomerular filtration rate [GFR] categories G3 to G5).
- Diuretic therapy.
- Tophi.
- Chronic gouty arthritis.
Discuss the option of ULT, using a treat-to-target strategy, with all other people experiencing a first or subsequent flare.
Explain that ULT is usually continued after the target serum urate level is reached and is typically a lifelong treatment, and discuss the benefits and risks of taking medicines to prevent gout flares when starting or titrating ULT.
Start ULT at least 2-4 weeks after a gout flare has settled.
- If flares are more frequent, ULT can be started during a flare.
Start with a low dose of ULT and use monthly serum urate levels to guide dose increases, as tolerated, until the target urate level is reached.
Aim for a target serum urate level below 360 micromol/L (6 mg/dL), but consider a lower target serum urate level below 300 micromol/L 6 (5 mg/dL) for people with gout who:
- Have tophi or chronic gouty arthritis.
- Continue to have ongoing frequent flares despite having a serum urate level below 360 micromol/L (6 mg/dL).
Offer allopurinol, or febuxostat first-line taking into account the person's preferences and comorbidities.
- Offer allopurinol first-line to people with gout who have major cardiovascular disease (for example, myocardial infarction, stroke, or unstable angina).
- Consider switching to second-line treatment with allopurinol or febuxostat if the target serum urate level is not reached or first-line treatment is not tolerated.
- Check liver function tests prior to initiation of febuxostat and consider screening for HLA-B*5801 before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high (for example people of Han Chinese, Thai and Korean origin).
Discuss with the person the benefits and risks of taking medicines to prevent gout flares when starting or titrating ULT.
Offer colchicine to people who choose to have treatment to prevent gout flares when starting or titrating ULT.
- If colchicine is contraindicated, not tolerated, or ineffective, consider a nonsteroidal anti-inflammatory drug (NSAID) or corticosteroid. Note: this is an off-label use of NSAIDs and corticosteroids.
- Consider adding a proton pump inhibitor for people with gout who are taking an NSAID to prevent a gout flare.
Do not offer an interleukin-1 (IL-1) inhibitor when starting or titrating ULT to prevent gout flares unless colchicine, NSAIDs and corticosteroids are contraindicated, not tolerated or ineffective. Refer the person to a rheumatology service before prescribing an IL-1 inhibitor.
Consider annual monitoring of serum urate level in people with gout who continue ULT after reaching their target serum urate level.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], the British Society for Rheumatology Guideline for the management of gout [Hui, 2017], the 2020 American College of Rheumatology Guideline for the management of gout [FitzGerald, 2020], the British National Formulary [BNF, 2022], and the manufacturer's Summary of Product Characteristics for Allopurinol [ABPI, 2022a].

Decision to start urate-lowering therapy(ULT)

The recommendations on when to offer ULT are based on the NICE guideline [NICE, 2022].
The American College of Rheumatology (ACR) recommends starting ULT for people [FitzGerald, 2020]:
- With 1 or more subcutaneous tophi.
- Radiographic evidence of damage attributable to gout.
- Who experience 2 or more gout flares per year.
- Who have experienced more than one flare but have infrequent flares (less than 2 a year), depending on patient-specific factors (for example, CKD, level of serum urate, cardiovascular disease).
- Experiencing their first flare and CKD stages 3 or higher, serum urate level over 9 mg/dL, or urolithiasis.

Choice of ULT

NICE recommends that people with gout should be offered allopurinol or febuxostat, and that allopurinol should be offered first-line for people with major cardiovascular disease because of the MHRA guidance on febuxostat in this population, but notes that this recommendation may change in the future [NICE, 2022].
- The MHRA advises that treatment with febuxostat should be avoided in people with pre-existing major cardiovascular disease (for example, myocardial infarction, stroke, or unstable angina), unless no other therapy options are appropriate. Findings from a phase 4 clinical study (the CARES study) in people with gout and a history of major cardiovascular disease show a higher risk for cardiovascular-related death and for all-cause mortality in patients assigned to febuxostat than in those assigned to allopurinol [MHRA, 2019].
- However, a recent study, Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST), which compared treatment with allopurinol and febuxostat in people with at least one additional cardiovascular risk factor found that long-term use of febuxostat was not associated with an increased risk of death or serious adverse events compared with allopurinol [Mackenzie, 2020].
ACR recommends initiating therapy with allopurinol in preference to all other ULTs, including in people with CKD stage 3 or higher [FitzGerald, 2020].
BSR also recommends allopurinol first-line [Hui, 2017] as does EULAR for people with normal kidney function [Richette, 2017].

Starting ULT

NICE recommends starting at a low dose of ULT 2-4 weeks after a gout flare has settled and discussing the benefits of taking medicines to prevent gout flares when starting or initiating ULT [NICE, 2022].
ACR recommends starting with a low dose (100 mg/day or lower for allopurinol and 40 mg or lower for febuxostat) then titrating up, and initiating concomitant anti-inflammatory prophylaxis therapy, with the choice based on patient factors. It also recommends that if ULT is indicated while the patient is experiencing a flare, starting treatment during the flare instead of waiting until it has resolved, although delaying treatment may be preferred for some people depending on patient-specific factors and preferences [FitzGerald, 2020].

Duration of ULT therapy

NICE recommends discussing the importance of long-term treatment, usually life-long, with people on ULT [NICE, 2022].
ACR strongly recommends continuing ULT therapy indefinitely to maintain the serum urate target [FitzGerald, 2020], and EULAR also recommends lifelong therapy [Richette, 2017].
The BSR guideline recommends that ULT therapy should be lifelong unless modifiable risk factors are successfully addressed and clinical cure is achieved [Hui, 2017].

Screening for HLA-B*5801

ACR makes a conditional recommendation for testing for the HLA–B*5801 allele prior to starting allopurinol for patients of Southeast Asian descent (for example, Han Chinese, Korean, Thai) and for African Americans as the allele is associated with a marked elevated risk of allopurinol hypersensitivity syndrome (AHS) [FitzGerald, 2020].
Allopurinol should not be used in people carrying the variant allele HLAB*5801 as the risk of severe cutaneous adverse reactions (SCAR) during treatment with allopurinol is greatly increased [Hui, 2017].
The manufacturer also advises screening should be considered before starting treatment with allopurinol in patient subgroups where the prevalence of this allele is known to be high [ABPI, 2022a].

Serum urate target

NICE, ACR and EULAR recommend a target serum urate level of less than 360 micromol/L (6 mg/dL) [NICE, 2022; FitzGerald, 2020; Richette, 2017].
However, BSR recommends an initial target of below 300 micromol/L, but advises that after years of successful treatment, when tophi have resolved and the patient remains symptom-free the dose of ULT can be adjusted to maintain the serum urate level at or below 360 micromol/L [Hui, 2017].
EULAR recommends a target rate below 300 micromol/L (5 mg/dL) for people with severe gout, and NICE recommends that a lower serum urate level of 300 micromol/L (5mg/dL) can be considered in people who:
- Have tophi or chronic gouty arthritis.
- Continue to have ongoing frequent flares despite having a serum urate level below 360 micromol/litre (6 mg/dL).

Duration of anti-inflammatory prophylaxis therapy

NICE recommends offering treatment to prevent gout flares while the target serum level is being reached [NICE, 2022].
BSR recommends that treatment should be continued for up to 6 months [Hui, 2017].
ACR recommends that concomitant anti-inflammatory prophylaxis therapy (with colchicine, NSAIDs, or corticosteroids) should be continued for 3-6 months with ongoing evaluation and thereafter treatment should be continued if the person continues to experience flares [FitzGerald, 2020].

What lifestyle advice should I give a person with gout?

Advise people with gout:
- To follow a healthy, balanced diet, and explain that there is not enough evidence to show that any specific diet prevents flares or lowers serum urate levels.
- That excess body weight, obesity or excessive alcohol consumption may exacerbate gout flares and symptoms.
If a gout flare occurs during treatment with allopurinol or febuxostat:
- Advise that they should treat the attack as soon as it occurs and that prophylactic treatment should not be discontinued.
- Manage the flare as appropriate for the person.
- Reassure the person that continuous treatment with allopurinol or febuxostat will decrease the frequency and intensity of further gout flares.
Provide written information and patient support such as resources via the UK Gout Society. For more information, see www.ukgoutsociety.org.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], the British Society for Rheumatology Guideline for the management of gout [Hui, 2017], and the 2020 American College of Rheumatology Guideline for the management of gout [FitzGerald, 2020].

NICE recommends that people with gout should follow a healthy balanced diet and it should be explained that there is not enough evidence to show that any specific diet prevents flares or lowers serum urate levels [NICE, 2022]. The BMJ best practice guide also advises that there is a paucity of high-quality evidence to support or refute the use of lifestyle modifications for improving outcomes in people with chronic gout [BMJ, 2021].
However, BSR recommends that people with gout should be advised to eat a well-balanced diet that is low in fat and added sugars, and high in vegetables and fibre, and that sugar-sweetened soft drinks containing fructose, excessive intake of alcoholic drinks, and high purine foods should be avoided. It also advises that inclusion of skimmed milk and/or low fat yoghurt, soy beans and vegetable sources of protein, and cherries in the diet should be encouraged [Hui, 2017].
The ACR makes conditional recommendations for limiting alcohol intake, purine intake, high-fructose corn syrup and using a weight loss program for people with gout who are overweight/obese [FitzGerald, 2020].
EULAR advises that lifestyle and dietary modification has little effect on urate concentration and the quality of evidence so support the effect of lifestyle modification is low, but given the high prevalence of cardiovascular comorbidities in patients with gout, lifestyle modifications should also be implemented as part of cardiovascular prevention [Richette, 2017].

What follow up is needed in someone taking urate-lowering therapy?

Check the serum urate level monthly and use it to guide dose increases, as tolerated, until it is within the target range.
If the person is still having frequent attacks of gout despite urate-lowering therapy (ULT):
- Assess compliance with prophylactic medication or increase the dose if appropriate.
- Review any trigger factors such as medication (for example diuretics), trauma, diet, weight gain, and excess alcohol consumption.
- Consider providing an advance prescription of effective treatment for future attacks of gout.
- Consider referral to secondary care.
Consider annual monitoring of serum urate level in people with gout who continue ULT after reaching their target serum urate level.
Monitor kidney function regularly in parallel with the serum urate measurement and screen for cardiovascular risk factors and comorbidities (including renal disease) at least annually.
- Offer testing for CKD using eGFRcreatinine and albumin:creatinine ratio (ACR).
For people taking:
- Allopurinol — monitor closely for hypersensitivity syndrome when therapy is initiated.
- Febuxostat — monitor liver function periodically, based on clinical judgement.
Provide ongoing lifestyle advice. For more information, see the CKS topic on CVD risk assessment and management.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guidelines Gout: diagnosis and management [NICE, 2022], Chronic kidney disease: assessment and management [NICE, 2021], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], the British Society for Rheumatology Guideline for the management of gout [Hui, 2017], the British Medical Journal BMJ Best Practice guide Gout [BMJ, 2021], the British National Formulary [BNF, 2022], the manufacturer's Summary of Product Characteristics for Febuxostat [ABPI, 2022b], and what CKS considers good medical practice.

Monitoring kidney function

EULAR recommends that the estimated glomerular filtration rate (eGFR) should be calculated at the time of diagnosis for CKD classification and monitored regularly in parallel with the serum urate measurement, as the EULAR taskforce agreed that identifying CKD in people with gout was of major importance because of the therapeutic implications [Richette, 2017].
The NICE guideline on chronic kidney disease recommends that testing for CKD should be offered to people with risk factors for CKD, including gout, and that the frequency of monitoring should be individualised [NICE, 2021].
BSR recommends screening people with gout annually for cardiovascular risk factors and comorbid conditions, such as renal disease [Hui, 2017].

When is referral recommended in someone with gout?

Refer the person immediately, according to the local care pathway if septic arthritis is suspected.
Refer to a specialist or seek specialist advice when:
- There is a suspicion of an underlying systemic illness (for example rheumatoid arthritis or connective tissue disorder), or gout occurs during pregnancy or in a young person (under 30 years of age).
- An intra-articular steroid injection is indicated but the facilities or expertise are not available in primary care.
- Complications are present.
- The person is at risk of adverse effects of drug treatment.
Consider referring a person with gout to a rheumatology service if:
- The diagnosis of gout is uncertain.
- The response to treatment has not been adequate or the treatment is not tolerated.
- Treatment is contraindicated.
- They have chronic kidney disease (CKD) stages 3b to 5 (GFR categories G3b to G5).
- They have had an organ transplant.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], and what CKS considers good medical practice.

Prescribing information

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC)), or the British National Formulary (BNF).

Nonsteroidal anti-inflammatory drugs

For prescribing information on NSAIDs, see the CKS topic on NSAIDs - prescribing issues.

Colchicine

Dose

For acute gout:
- Prescribe 500 micrograms of colchicine 2-4 times daily, until pain relief is achieved.
- The manufacturer recommends a dose of 1 mg to start followed by 500 micrograms after 1 hour, leaving a gap of 12 hours, and resuming treatment with 500 micrograms every 8 hours until symptoms are relieved.
- The maximum dose per course is 6 mg and the course should not be repeated within 3 days.
For prophylaxis of gout flares (during urate-lowering treatment):
- Give 500 micrograms of colchicine twice daily following initiation of long-term treatment with allopurinol or febuxostat.
- Decide treatment duration taking into account factors such as flare frequency, gout duration and the presence and size of tophi.
In the elderly or people with an eGFR of 10-50 mL/minute/1.73m² reduce dose or increase the dosage interval. Colchicine is contraindicated in people with an eGFR less than 10 mL/minute/1.73m².

[Hui, 2017; ABPI, 2021; BNF, 2022]

Contraindications and cautions

Do not prescribe colchicine to people:
- With blood disorders.
- With severe renal impairment or severe hepatic impairment.
Prescribe colchicine with caution in the elderly and people with:
- Abnormal blood counts.
- Cardiac disease.
- Gastrointestinal disease.
- Mild to moderate hepatic impairment.
- Renal impairment — reduce dose or increase dosage interval if estimated glomerular filtration rate (eGFR) is 10-50 mL/minute/1.63m².

[ABPI, 2021; BNF, 2022]

Adverse effects

Common adverse include:

Nausea and vomiting.
Abdominal pain.
Diarrhoea.

Other adverse effects include:

Bone marrow depression with aplastic anaemic, agranulocytosis, leukopenia or thrombocytopenia.
Alopecia.
Sperm abnormalities.
Menstrual irregularities.
Myopathy and peripheral neuritis.
Rashes, vesicular dermatitis.

Colchicine has a narrow therapeutic index and is extremely toxic in overdose.

Early features (up to 1 day after ingestion) include nausea, vomiting, abdominal pain, and diarrhoea. Diarrhoea may be profuse and bloody, and the patient may present with electrolyte disturbances and hypovolaemic shock.
Features after 1–7 days include confusion, decreased cardiac output, cardiac arrhythmias, renal and hepatic impairment, respiratory distress, hyperpyrexia, and bone-marrow depression. This can progress in severe cases to include multiple organ failure with accompanying bone-marrow aplasia, convulsions, coma, rhabdomyolysis, and disseminated intravascular coagulation.
People at particular risk of toxicity are those with renal or hepatic impairment, gastrointestinal or cardiac disease, and patients at extremes of age.
Colchicine overdose is complex and specialist advice should be promptly obtained.
There is often a delay of up to 6 hours before toxicity is apparent, and some features of toxicity may be delayed by 1 week or longer.
All people, even in the absence of early symptoms, should be referred for immediate medical assessment.

[MHRA, 2014a; ABPI, 2021; BNF, 2022]

Drug interactions

P-glycoprotein inhibitors (for example, macrolide antibiotics, ritonavir, verapamil) — exposure to colchicine is increased, potentially leading to life-threatening toxicity. Monitor for clinical symptoms of colchicine toxicity. Concurrent use is contraindicated in people with renal or hepatic impairment.
Strong CYP3A4 inhibitors (for example, macrolide antibiotics, nefazodone, azole antifungals, HIV protease inhibitors) — exposure to colchicine may be increased.
Ciclosporin — concurrent use increases colchicine exposure, increasing the risk of muscle toxicity. Consider stopping colchicine temporarily or if concurrent use is necessary, reduce colchicine dose. Concurrent use is contraindicated in renal or hepatic impairment.

[ABPI, 2021; Preston, 2023]

Corticosteroids

What issues do I need to consider when prescribing a corticosteroid?

For prescribing information on corticosteroids, see the CKS topic on Corticosteroids - oral.

Allopurinol

Dose

Prescribe a low starting dose of allopurinol 100 mg or less once daily (preferably taken after food) and adjust dose in 100 mg increments every 4 weeks according to plasma or serum urate level.
- 100-200 mg daily in mild conditions.
- 300-600 mg daily in moderately severe conditions.
- 700-900 mg daily in severe conditions.
Doses of over 300 mg daily should be taken in divided doses to help minimize any gastrointestinal adverse effects with maximum of 300 mg per dose.
Use a reduced dose in:
- Elderly people — use the lowest dose that produces satisfactory urate reduction.
- People with hepatic impairment — monitor liver function in the early stages of treatment.
In people with renal impairment, prescribe a maximum initial dose of 100 mg and increase only if the response is inadequate.
- In severe impairment, reduce daily dose below 100 mg, or increase the dose interval.

[Hui, 2017; ABPI, 2022a; BNF, 2022; FitzGerald, 2020]

Contraindications and cautions

Do not prescribe allopurinol to people:
- Known to have the HLA-B*5801 allele — it is associated with the risk of developing allopurinol hypersensitivity syndrome and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN).
  - Screening should be considered in people from ethnic groups where prevalence of the allele is known to be high (for example Han Chinese, Thai and Korean populations).
Prescribe allopurinol with caution to people with:
- Thyroid disorders.
- Hepatic impairment.
- Renal impairment.

[ABPI, 2022a] [BNF, 2022]

Adverse effects

Common adverse effects include:

Rash — advise people who experience a rash to stop allopurinol immediately and seek prompt medical advice.
- Rarely, exfoliative rashes such as Stevens Johnsons syndrome (SJS) or toxic epidermal necrolysis (TEN) can occur. A rash can be the first sign of a rare hypersensitivity reaction.
- If SJS/TEN or a serious hypersensitivity reaction cannot be ruled out, allopurinol should not be re-introduced at any time. If the rash was mild and subsequently resolved, gradually reintroduce the allopurinol. If the rash recurs, immediately discontinue the allopurinol.
Thyroid stimulating hormone level increases.

Other adverse effects include:

Gout flares — there is a risk of precipitating acute attacks of gout after starting allopurinol.
- Advise people who experience acute attacks of gout after initiation of treatment with allopurinol, or during established treatment, to continue taking allopurinol.
Hypersensitivity.
Liver dysfunction
Nausea, vomiting, diarrhoea.

[ABPI, 2022a; BNF, 2022]

Drug interactions

Angiotensin-converting enzyme (ACE) inhibitors (captopril, enalapril) — concurrent use may increase the risk of hypersensitivity, or blood dyscrasias. Monitor for signs of hypersensitivity or low white cell count, especially if the person has renal impairment.
- Monitor white blood cell counts before starting allopurinol, then every 2 weeks during the first 3 months of concurrent use, and periodically thereafter.
Aluminium hydroxide — effects of allopurinol may be reduced if taken concurrently with aluminium hydroxide. Advise people to separate doses by 3 hours or more.
Azathioprine — concurrent administration with allopurinol increases the haematological adverse effects of azathioprine. Reduce normal dose of azathioprine to one-quarter, monitor full blood count and advise people to report any signs or symptoms of bone marrow suppression (unexplained bruising, or bleeding, sore throat, fever).
Carbamazepine — levels may be increased with concurrent use of high doses of allopurinol (15 mg/kg or 600 mg daily). Advise people to monitor for adverse effects.
Cyclophosphamide — possible increased risk of bone marrow suppression if taken concurrently with allopurinol.
Furosemide — levels of an active metabolite of allopurinol may be increased. Use with caution, especially in people with renal impairment.
Thiazide diuretics (bendroflumethiazide) — increased risk of severe allergic reactions, especially in people with renal impairment.
Warfarin and other coumarins — prothrombin time may be increased if taken concurrently with allopurinol. Consider increasing the frequency of INR monitoring.

[Preston, 2023]

Febuxostat

Dose

Prescribe a low starting dose of febuxostat 80 mg or less once daily for 2-4 weeks, then if serum urate level is greater than 6 mg/100 mL increase dose to a maximum of 120 mg once daily.
- In people with mild hepatic impairment the maximum daily dose is 80 mg.
  - There is limited information available in people with more severe hepatic impairment.
- No dose adjustment is needed for the elderly, or those with mild or moderate renal impairment.
  - Febuxostat has not been fully evaluated in people with severe renal impairment (creatinine clearance less than 30 mL/min).
- Prescribe for at least 6 months when starting febuxostat.
Co-prescribe an NSAID or colchicine for at least 6 months after starting febuxostat to avoid precipitating an acute attack of gout.

[ABPI, 2022b; BNF, 2022]

Contraindications and cautions

Prescribe febuxostat with caution to organ transplant recipients, and people with:
- Cardiovascular disorders (for example myocardial infarction, stroke or unstable angina), particularly in those with evidence of high urate crystal and tophi burden or those initiating urate-lowering therapy [MHRA, 2023].
- Hepatic impairment.
  - Monitor liver function before starting treatment and periodically during treatment.
- Renal impairment.
- Thyroid disorders.

[MHRA, 2019; ABPI, 2022b; BNF, 2022]

Adverse effects

Common adverse effects include:

Arthralgia, myalgia.
Diarrhoea, nausea.
Dyspnoea.
Fatigue.
Gout flares — there is a risk of precipitating acute attacks of gout after starting febuxostat.
- Advise people who experience acute attacks of gout after initiation of treatment with febuxostat, or during established treatment, to continue taking febuxostat.
Headache, dizziness.
Liver function abnormalities.
Oedema.
Rash, pruritus.
- Rarely, serious hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and anaphylactic reaction/shock have been reported.

The Medicines and Healthcare products Regulatory Agency (MHRA) advises that [MHRA, 2014b]:

Febuxostat should be stopped immediately if signs or symptoms of serious hypersensitivity reactions occur; early withdrawal is associated with a better prognosis.
If a hypersensitivity reaction occurs with febuxostat it must not be re-started at any time.
Most cases of hypersensitivity to febuxostat occur during the first month of treatment.
Patients should be advised of signs and symptoms of severe hypersensitivity or Stevens-Johnson syndrome. These include:
- Infiltrated maculopapular eruption.
- Generalised or exfoliative rashes.
- Skin lesions.
- Facial oedema.
- Fever.
- Haematologic abnormalities such as thrombocytopenia.
- A single or multiple organ involvement (liver and kidney including tubulointerstitial nephritis).
- Progressive skin rashes associated with blisters or mucosal lesions and eye irritation.
A prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat.

[BNF, 2022; ABPI, 2022b]

Drug interactions

Aminophylline, theophylline — levels may be increased if taken concurrently with febuxostat. Monitor for signs of adverse effects (headache, nausea, tremor), monitor theophylline concentrations and adjust dose if necessary.
Mercaptopurine, azathioprine — levels of these drugs may be increased. Concurrent use is not recommended, but if it cannot be avoided, reduce dose of mercaptopurine/azathioprine to 20% or less of the previously prescribed dose.

[ABPI, 2022b; Preston, 2023]

Paracetamol

For prescribing information on paracetamol, see the CKS topic on Analgesia - mild-to-moderate pain.

Supporting evidence

This CKS topic is largely based on the National Institute for Health and Care Excellence (NICE) guideline Gout: diagnosis and management [NICE, 2022], the British Medical Journal (BMJ) Best Practice guide Gout [BMJ, 2021], the 2018 updated European League Against Rheumatism (EULAR) evidence-based recommendations for the diagnosis of gout [Richette, 2020], the 2016 updated EULAR evidence-based recommendations for the management of gout [Richette, 2017], the British Society for Rheumatology Guideline for the Management of Gout [Hui, 2017], and the 2020 American College of Rheumatology Guideline for the management of gout [FitzGerald, 2020]. The rationale for the individual recommendations is discussed in the relevant basis for recommendation sections.

How this topic was developed

This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of gout.

Search dates

October 2017 - June 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Gout/, gout.tw.

Sources of guidelines

Sources of systematic reviews and meta-analyses

The Cochrane Library:
- Systematic reviews
- Protocols
- Database of Abstracts of Reviews of Effects
Medline (with systematic review filter)
EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme
The Cochrane Library:
- NHS Economic Evaluations
- Health Technology Assessments
Canadian Agency for Drugs and Technologies in Health
International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library:
- Central Register of Controlled Trials
Medline (with randomized controlled trial filter)
EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Sources of national policy

Department of Health
Health Management Information Consortium (HMIC)

Patient experiences

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

Clinical accuracy.
Consistency with other providers of clinical knowledge for primary care.
Accuracy of implementation of national guidance (in particular NICE guidelines).
Usability.

Principles of the consultation process

The process is inclusive and any individual may participate.
To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
External reviewers are not paid for commenting on the draft topics.
Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
Stakeholders identified from the following groups are invited to review draft topics:
- Experts in the topic area.
- Professional organizations and societies (for example, Royal Colleges).
- Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
- Guideline development groups where the topic is an implementation of a guideline.
- The British National Formulary team.
- The editorial team that develop MeReC Publications.
Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

Topic selection
Scoping of topic
Selection of clinical scenarios
First draft internal review
Second draft internal review
External review
Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

Animal studies
Original research is not written in English

Possible exclusions for reviewed literature:

Sample size too small or study underpowered
Bias evident or promotional literature
Population not relevant
Intervention/treatment not relevant
Outcomes not relevant
Outcomes have no clear evidence of clinical effectiveness
Setting not relevant
Not relevant to UK
Incorrect study type
Review article
Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

Feasibility
- Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
Organizational and Financial Impact Analysis
Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
- Eligible population
- Current interventions
- Likely uptake of new intervention or recommendation
- Cost of the current or new intervention mix
- Impact on other costs
- Condition-related costs
- In-direct costs and service impacts
- Time dependencies
Cost-effectiveness or cost-benefit analysis studies are identified where available.

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

Personal financial interests
Personal family interest
Personal non-financial interest
Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.

References

ABPI (2021) SPC for Colchicine Tablets BP 500 mcg. Electronic Medicines Compendium. Datapharm Communications Ltd. https://www.medicines.org.uk/emc [Free Full-text]
ABPI (2022a) SPC for Allopurinol 300mg Tablets. Electronic Medicines Compendium. Datapharm Communications Ltd. https://www.medicines.org.uk/emc [Free Full-text]
ABPI (2022b) SPC for Febuxostat 80mg film-coated tablets. Electronic Medicines Compendium. Datapharm Communications Ltd. https://www.medicines.org.uk/emc [Free Full-text]
BMJ Best Practice (2021) Gout. BMJ Publishing Group. https://bestpractice.bmj.com
BNF (2022) British National Formulary. National Institute for Health and Care Excellence (NICE). https://bnf.nice.org.uk
Campion, E.W., Glynn, R.J. and DeLabry, L.O. (1987) Asymptomatic hyperuricemia: risks and consequences in the Normative Aging Study. American Journal of Medicine 82(3), 421-426. [Abstract]
Cox, P., Gupta, S., Zhao, S. et al. (2021) The incidence and prevalence of cardiovascular diseases in gout:a systematic review and meta‑analysis. Rheumatology International 41(7), 1209-1219. [Abstract]
Dalbeth, N., Merriman, T. and Stamp, L. (2016) Gout. Lancet 388(10055), 2039-2052. [Abstract]
FitzGerald, J.D., Dalbeth, N., Mikuls, T. et al. (2020) 2020 American College of Rheumatology Guideline for the management of gout. Arthritis Care and Research 72(6), 744-760. [Abstract]
Hainer, B., Matheson, E. and Wilkes, R. (2014) Diagnosis, treatment, and prevention of gout. American Family Physician 90(12), 831-836. [Abstract]
Hui, M., Carr, A., Cameron, S., et al. (2017) The British Society for Rheumatology Guideline for the Management of Gout. Rheumatology 56(7), 1-20. [Abstract] [Free Full-text]
Kuo, C., Grainge, M., Mallen, C. and et al. (2015) Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Annals of the Rheumatic Diseases 74(4), 661-667. [Abstract]
Mackenzie, I.S., Ford, I., Nuki, G. et al. (2020) Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST). Lancet 396(10264), 1745-1757. [Abstract]
MHRA (2014a) Colchicine: extremely toxic in overdose. Medicines and Healthcare products Regulatory Agency. https://www.gov.uk [Free Full-text]
MHRA (2014b) Febuxostat (Adenuric): stop treatment if signs or symptoms of serious hypersensitivity. Medicines and Healthcare products Regulatory Agency. https://www.gov.uk [Free Full-text]
MHRA (2019) Febuxostat (Adenuric): increased risk of cardiovascular death and all-cause mortality in clinical trial in patients with a history of major cardiovascular disease. Medicines and Healthcare products Regulatory Agency. https://www.gov.uk [Free Full-text]
MHRA (2023) Febuxostat: updated advice for the treatment of patients with a history of major cardiovascular disease. Medicines and Healthcare products Regulatory Agency. https://www.gov.uk [Free Full-text]
NICE (2021) Chronic kidney disease: assessment and management. National Institute for Health and Care Excellence. https://www.nice.org.uk [Free Full-text]
NICE (2022) Gout: diagnosis and management. National Institute for Health and Care Excellence. https://www.nice.org.uk [Free Full-text]
Nuki, G. (2006) Gout. Medicine 34(10), 417-423.
Preston, C.L. (2023) Stockley's Drug Interactions. Medicines Complete. Pharmaceutical Press. https://www.new.medicinescomplete.com
Richette, P., Doherty, M., Pascual, E., et al. (2017) 2016 updated EULAR evidence-based recommendations for the management of gout. Annals of the Rheumatic Diseases 76(1), 29-42. [Abstract]
Richette, P., Doherty, M., Pascual, E. et al. (2020) 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Annals of the Rheumatic Diseases 79(1), 31-38. [Abstract] [Free Full-text]
Roddy, E., Mallen, C. and Doherty, M. (2013) Gout. British Medical Journal 343, 5648.
Roddy, E. and Doherty, M. (2020) Crystal-related arthropathies. In: Firth, J., Conlon, C. and Cox, T. (Eds.) Oxford Textbook of Medicine. 6th edn.
Roughley, M., Belcher, J., Mallen, C. and et al. (2015) Gout and the risk of chronic kidney disease and nephrolithiasis: meta-analysis of observational studies. Arthritis Research & Therapy 17, 90. [Abstract]
Safiri, S., Kolahi, A-A., Cross, M. et al. (2020) Safiri, 2020, Prevalence, incidence, and years lived With disability due to gout and its attributable risk factors for 195 countries and territories 1990–2017: a systematic analysis of the global burden of disease study 201. Arthritis and Rheumatology 72(11), 1916-1927. [Abstract]
Singh, J.A., Reddy, S.G. and Kundukulam, J. (2011) Risk factors for gout and prevention: a systematic review of the literature. Current Opinion in Rheumatology 23(2), 192-202. [Abstract]
Sivera, F., Andrés, M., Carmona, L. et al. (2014) Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative. Annals of the rheumatic diseases 73(2), 328-335. [Abstract] [Free Full-text]
Wijnands, J., Viechtbauer, W. and Thevissen, K. et al. (2015) Determinants of the prevalence of gout in the general population: a systematic review and meta-regression. European Journal of Epidemiology 30(1), 19-33. [Abstract]

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Gout: Summary

Have I got the right topic?

How up-to-date is this topic?

Changes

Previous changes

Update

New evidence

Evidence-based guidelines

HTAs (Health Technology Assessments)

Economic appraisals

Systematic reviews and meta-analyses

Primary evidence

New policies

New safety alerts

Changes in product availability

Goals and outcome measures

Goals

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

NICE quality standards

Background information

What is it?

What are the causes and risk factors for gout?

How common is it?

What are the complications?

What is the prognosis?

Diagnosis of gout

When should I suspect a person has gout?

Basis for recommendation

How should I assess a person with suspected gout?

What are the American College of Rheumatology criteria for diagnosing gout?

Basis for recommendation

What investigations should I consider?

Basis for recommendation

Serum urate level

Joint aspiration

What else might it be?

Basis for recommendation

Management

Scenario: Acute gout

How should I manage a person with acute gout?

Basis for recommendation

Managing flares

Oral corticosteroid dose

What follow up is recommended after an acute attack of gout?

Basis for recommendation

Screening for comorbidities

When should I refer?

Basis for recommendation

Scenario: Preventing gout